Non-invasive neuromodulation (NINM) for rehabilitation of brain function

ABSTRACT

A method to provide non-invasive neurostimulation to enhance a subject&#39;s proficiency in an exercise includes: (a) engaging a subject in an exercise, the subject having no cognitive, physical or emotional impairment with respect to the exercise; (b) providing stimulation of at least one of the subject&#39;s trigeminal nerve, facial nerve or hypoglossal nerve by delivering electrical pulses generated by a signal generator to the subject&#39;s skin via at least one electrode in contact with the subject&#39;s skin, the delivery of electrical pulses being (i) contemporaneously with and independent of the subject&#39;s engagement in the exercise, and (ii) independent of the subject&#39;s surrounding environment; and (c) repeating steps (a) and (b) on a periodic basis.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of, claims priority to and thebenefit of, and incorporates by reference herein in its entirety, U.S.patent application Ser. No. 14/815,171 filed Jul. 31, 2015, which is acontinuation of U.S. patent application Ser. No. 14/689,462, filed Apr.17, 2015, which is a continuation of U.S. patent application Ser. No.14/341,141, filed Jul. 25, 2014 and issued as U.S. Pat. No. 9,020,612 onApr. 28, 2015, which is a continuation of U.S. patent application Ser.No. 14/340,144, filed Jul. 24, 2014, and issued as U.S. Pat. No.8,909,345 on Dec. 9, 2014, which is a continuation of U.S. patentapplication Ser. No. 12/348,301, filed Jan. 4, 2009, and issued as U.S.Pat. No. 8,849,401 on Sep. 30, 2014, which claims the benefit of andpriority to U.S. Provisional Application No. 61/019,061 filed Jan. 4,2008 and U.S. Provisional Application No. 61/020,265 filed Jan. 10,2008, the entireties of which are incorporated by reference herein.

STATEMENT OF GOVERNMENT INTEREST

The subject matter described herein was developed in connection withfunding provided by the National Institutes of Health under Grant No.NS048903. The Government may have certain rights in the invention.

FIELD OF THE INVENTION

This document concerns an invention relating generally to treatment ofneurological impairments, and more specifically to methods and devicesfor enhancing neurorehabilitation.

BACKGROUND OF THE INVENTION

Neurorehabilitation is an emerging field in medical science whereinpatients suffering from damage to, or impairment of, all or a portion oftheir central nervous system (CNS) are treated to rehabilitate neuralpathways, and/or establish new neural pathways, to at least partiallycompensate for the damage/impairment. Neurorehabilitation is thereforesomewhat different from neural substitution, where devices are used totry to provide new neural inputs which serve as a proxies for impairedneural inputs—for example, devices which collect images of a patient'ssurroundings and then provide tactile feedback to the patient independence on the collected images, such that the patient is giventactile input as a substitute for visual input. Examples of neuralsubstitution devices are described in prior patent applications whichname the inventors of the present invention, e.g., US Published PatentAppins. 20050240253, US20060161218, 20060241718, 20070250119,20080009772, and 20080228239 (all of which are incorporated by referenceherein).

At the time this document was prepared, neurorehabilitation was commonlyeffected by non-invasive methods such as physical therapy, occupationaltherapy, or speech therapy, which basically involves the use of exerciseto attempt to increase a patient's abilities. For example, one sufferingfrom a spinal cord injury might exercise an affected area of the body toincrease coordination and range of motion. These methods suffer from thedisadvantage of being time-consuming, difficult and exhausting for thepatient. Invasive methods also exist, such as electrostimulation,wherein electrodes are implanted to deliver electricity at or nearneural pathways to enhance neural function, and/or to counter“erroneous” neural function. For example, deep brain stimulation (DBS)may be used for treatment of Parkinson's Disease and depression, leftvagal nerve stimulation (LVNS) may be used for treatment of epilepsy, orsub-dural implantable stimulators may be used to assist with strokerecovery. These invasive methods are risky, still largely experimental,and expensive, and thus are generally used as a last resort when allother therapeutic interventions have failed. Additionally, they have notyet proven to be generally usable with other severe CNS disorders suchas traumatic brain injury, stroke, or a sensory-motor polytraumaexperienced by wounded military personnel, for example. It wouldtherefore be useful to have additional methods and devices available forneurorehabilitation which are noninvasive or minimally invasive,inexpensive, and which eliminate or reduce the need for the ordeal ofphysical therapy and similar noninvasive methods.

SUMMARY OF THE INVENTION

The invention, which is defined by the claims set forth at the end ofthis document, is directed to methods—generally referred to herein as“non-invasive neuromodulation” or NINM—and NINM devices which at leastpartially alleviate the aforementioned problems. A basic understandingof some of the features of preferred versions of the invention can beattained from a review of the following brief summary of the invention,with more details being provided elsewhere in this document.

It has been found that neurorehabilitation can be assisted in a patientby having the patient engage in a task wherein the patient's ability toperform the task is hindered by impairment of the user's nervous system,and at the same time stimulating the patient's head and/or neck (or morespecifically, providing stimulation detectable by one or more branchesof the trigeminal nerve). For example, stimulation might be provided tothe patient's face, tongue, forehead, ears, scalp, or neck while thepatient attempts to maintain a normal posture, in the event of a patientwith vestibular dysfunction (i.e., having difficulties with balanceowing to impairment of the vestibular system); or while the patientmoves his/her limb(s), in the case of apraxia (i.e., impairment of theability to make purposeful/planned movement); or while the patientundergoes speech exercises, in the case of dysarthria (i.e., impairedspeaking). It has been found that such stimulation can expediteneurorehabilitation, with the patient's ability to successfully performthe task being enhanced for at least some period of time after thestimulation ceases. Thus, for example, it has been found that wherepatients with vestibular dysfunction are subjected to stimulation whilepracticing posture/gait exercises, and they then cease the exercises andstimulation, their vestibular function is improved for at least a periodof time thereafter, and for a longer period of time than if thestimulation was not provided. Thus, the foregoing methodology can beused to enhance the efficacy of conventional therapy.

The stimulation is preferably provided to the patient cutaneously (i.e.,upon the patient's skin) so that it is noninvasive, though subcutaneousstimulation is also possible. The stimulation is preferably delivered bythe use of stimulators, e.g., electrical elements (e.g., electrodes) fordelivery of electrical stimulation, mechanical/electromechanicalactuators (preferably piezo actuators, shape metal alloy actuators, MEMSactuators, or other compact devices), thermal elements (e.g., resistanceheating elements or Peltier/Seebeck/Thomson elements), and/orelectromagnetic elements (i.e., elements for emitting electromagneticenergy in the visible or invisible spectrum, e.g., radio wave emitters,microwave emitters, infrared emitters, ultraviolet emitters, etc.). Inall cases, stimulation is delivered at intensities such that it isdetectable by the patient's nerves, but at the same time such thattissue damage is avoided. Electrodes have been found to work well inpractice, and are particularly preferred types of stimulators. Thesestimulators might be arrayed across all or a portion of one or more of amask, a collar, a mouthpiece, or the like. As examples of masks, thesecould be provided in the form of a domino mask, ski mask, or othercommon mask; in the form of pads/patches covering all or some of thecheeks, chin, upper lip, nose, forehead, or other portions of the headand/or neck; or in the form of a cap/helmet masking portions of the headaway from the face and neck (and perhaps masking portions of the faceand/or neck as well). Collars could take the form of (for example)sleeves/bands covering some or all of the neck, and/or some or all ofthe forehead, or a portion of the face. As examples of mouthpieces,these might be provided in the form of a retainer, a mouthguard, or thelike. Thus, such a device might simply be put on by a patient for wearduring exercises, without the need for intrusive measures or otherburdensome or painful procedures.

Stimulation is preferably generated by a pattern generator whichdelivers stimulation (e.g., electrical pulses) in a random pattern, orin a repeating pattern such as brief pulses provided at a regularfrequency. It is notable that the stimulation pattern need not, andpreferably does not, rely on any feedback from the patient and/or thepatient's surroundings—for example, the stimulation pattern need not bevaried if the patient is monitored and it is determined that the patientis having difficulty with the task (or conversely if the patient isperforming the task well). Thus, the pattern generator can simply be setto a random or predetermined pattern by a therapist or by the patient,and the stimulators can continue to deliver this same preset pattern asthe patient performs the task (and for any post-task stimulation periodthereafter). The pulses are preferably delivered to the patient abovethe patient's threshold of sensory perception (i.e., such that thepatient can feel them), but below the level of discomfort. However, itis believed that the invention may also yield results if the pulses aredelivered to the patient just below the patient's threshold ofperception (i.e., such that the patient does not notice them, at leastunless the patient concentrates on feeling them).

It has been found that improvement in patients' abilities seems to bebest effected if the following methodology is followed. Initially, whilestimulation is supplied to the patient, the patient is made to performthe difficult task (one hindered by neural impairment) at low intensity.This is believed to provide the patient with confidence and proficiency,and can be performed for a short time period (e.g., for 5 minutes). Thepatient is then made to perform the task at high intensity, preferablyat the limit of their ability, in conjunction with stimulation.Assistance can be provided if needed, and this step can also beperformed for a short time period (e.g., for 5 minutes). The patientthen performs the task at moderate intensity in conjunction withstimulation, again for a short time period (e.g., for 5 minutes).Finally, after a short rest, the patient might undergo a period ofstimulation (e.g., for 20 minutes) during which the task is againperformed at moderate intensity. This routine is preferably performedtwice per day, with a span of about four hours separating the sessions.It is also notable that the invention also appears to improve cognitionand mood in at least some cases, i.e., the invention may also be usefulfor treatment of conditions such as learning, attention, and/or memorydisorders (e.g., Alzheimer's disease, attention deficit disorder, etc.),as well as mood disorders (e.g., depression, post-traumatic stressdisorder, obsessive-compulsive disorder, etc.).

Further advantages, features, and objects of the invention will beapparent from the remainder of this document in conjunction with theassociated drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a simplified signal flow chart of an exemplary version of theinvention wherein stimulation is applied to a patient independently ofany activity associated with a brain dysfunction or other neuralimpairment;

FIG. 2 is a simplified signal flow chart similar to that of FIG. 1 inwhich the stimulation is synchronized with an activity and/or externalstimuli related to the neural impairment;

FIG. 3 is a simplified signal flow chart similar to that of FIG. 1wherein the stimulation is simply contemporaneous with an activityassociated with the neural impairment.

DETAILED DESCRIPTION OF PREFERRED VERSIONS OF THE INVENTION

To expand on the discussion above, FIG. 1 illustrates an exemplaryversion of the invention wherein a facial mask 12 or tongue plate 14bears a set of spatially arrayed electrical, mechanical, thermal,electromagnetic, or other stimulators 17, such as electrodes. Thesestimulators 17 preferably provide stimulation to the trigeminal nerve orsubportions thereof, e.g., to the lingual nerve, and thereby stimulatethe brain. Such stimulation is preferably non-invasive, that is, indistinction from brain-penetrating electrodes or other matter whichpenetrates or otherwise modifies the flesh, and is most preferablycutaneous (i.e., effected by stimulators 17 which simply rest in contactwith the skin).

The facial mask 12 or tongue plate 14 may communicate with a patterngenerator 16 to energize the stimulators to stimulate the brain 18. Thepattern generator 16 may generate a regular or random stimulationpattern independent of the environment or other sensory input to, orresponse by, the patient.

FIG. 2 illustrates an alternative version of the invention wherein thedevice may provide feedback 19 from a sensor 20, for example, a sensormonitoring a patient activity such as movement of a limb or the like.The sensor 20 may also or alternatively monitor an external event 21related to the environment and possibly related to patient activity, forexample, describing a lever that the patient must grasp. The output ofthe sensor 20 may be received by a controller 23 that may provide anaudio, video or other sensory signal 24 back to the patient, forexample, so that the patient might better know the status of his/herperformance of the activity. The controller 23 may also synchronize thepattern generator 16 with the external signal 21 or feedback signal 19as indicated by process block 25 so that the stimulation may be linkedto particular activities by the patient or stimuli from the externalenvironment, for example, if it appears that the patient's performanceis substandard. The patient activity generating the feedback signal 19and the external signal 21 is preferably related to the neural pathwaysto be rehabilitated. For example, the feedback signal 19 may measure amuscular tremor related to impairment such as Parkinson's disease,multiple sclerosis, autism, Alzheimer's disease, vertigo, depression, orinsomnia. It is believed that this non-invasive neuromodulation 15,together with the sensory signals 24 from the activity itself, primes orup regulates those neurons of the brain 18 associated with the activity22 and thereby encourages a therapeutic rehabilitation of the affectedareas of the brain 18.

FIG. 3 shows another exemplary version of the invention wherein thestimulation of the non-invasive neuromodulation 15 is independent fromand unsynchronized with the sensory signals 24 produced by the activity30, although it occurs contemporaneously with the activity 30. In thiscase the sensor 20 might, for example, be a finger cuff bearingaccelerometers whose output is processed by a controller to providesensory signals 24 (here a trajectory display on a terminal 25). At thesame time, stimulation may be driven by the pattern generator 16independently from the sensory signals 24. As noted previously, thetherapeutic effects provided by the non-invasive neuromodulation 15 tendto continue after the non-invasive neuromodulation 15 ceases.

As previously noted, the pulses delivered by the stimulators can berandom or repeating. The location of pulses can be varied across thestimulator array such that different stimulators are active at differenttimes, and the duration and/or intensity of pulses may vary fromstimulator to stimulator. It is believed that the nature of the pulsesis not as important as the simple fact that the pulses are deliveredduring a task for which the patient wishes to improve his/herperformance. The pulses therefore need not be delivered in dependence onany factors occurring outside the device during delivery of theelectrical pulses, i.e., the pulses need not be delivered or varied inresponse to the quality of the patient's performance of the task.However, if desired, the pattern generator might receive feedback fromthe patient and/or the patient's environment, and might somehow modifypulse delivery in response. For example, more stimulation (e.g., pulsefrequency and/or intensity) might be provided if it is detected that thepatient's performance of the task is suffering rather than improving.

In practice, stimulation which delivers repeating pulses in the natureof a simple waveform, e.g., a square wave or series of regularly-spacedpulses, has been found to be effective. Also preferred are “bursts” ofpulses which repeat at some frequency, with the pulses within the burstsrepeating at a higher frequency (for example, as if the peaks or “on”periods of a square wave or other waveform were themselves formed of aseries of pulses). The fundamental or harmonic frequency underlying thestimulation waveform may be chosen in dependence on the particularapplication. As examples, testing and/or inference suggest that theappropriate frequency for sensory dysfunction might be around 40 Hz; forParkinson's disease, around 30-50 Hz; for involuntary movement/tremor,around 1-40 Hz; for voluntary movement coordination, around 50-100 Hz;for cognitive processes, around 100-300 Hz; for bradykinesia, around 150Hz; for sleep or anesthesia, around 80 Hz; and for relaxation orwakefulness, around 0.5-2.0 Hz. In some applications, it may be mosteffective to have the delivery frequencies of certain electrodes (orother actuators/elements for delivering stimulation) differ inaccordance with their location, e.g., electrodes in one area may deliverstimulation at one frequency and electrodes at another area deliverstimulation at another frequency (wherein the frequencies need notnecessarily have a harmonic relationship).

As also previously noted, stimulation may be provided by electrical,mechanical, thermal, or electromagnetic actuators/elements, which mayvary in their sizes and geometric configurations. Electrodes used intesting have typically been circular electrodes measuring between 1-10mm in diameter, but electrodes may be differently sized and configuredas desired. Cutaneous electrical stimulation of cranial nerve brancheshas been efficiently and inexpensively delivered using surfaceelectrodes held gently against the skin or oral tissue using masks(including full or partial facial masks, e.g., patches or frameworkscovering a portion of the face) and collars (including both neck collarsand bands/sleeves fitting about portions of the head) which preferablysituate the electrodes thereon to at least partially conform to thecontours of the skin surface over which they are placed. The electrodematerial may be chosen to minimize corrosion and skin irritation, withpossible electrode materials including gold, titanium, platinum,rhodium, and/or stainless steel. The electrode surface material may befull-thickness or a thin layer deposited by electroplating, vapordeposition, ion implantation, or similar processes. The electrode may beconductive, or possibly insulating so that only a capacitivedisplacement current flows into the skin. Insulating materials includevarious oxides of silicon, titanium, strontium, and/or tin, as well asvarious polymers such as polyester, polyimide, and/or polyamide-imide.Both mechanical and electrical contact between the electrode and skinmay be further enhanced by the use of electrically conductive materialssuch as electrode gels (with or without conductive electrolytes) ordistensible conductive polymers. Both gels and polymers may additionallyhave adhesive properties to further improve the electrode-skininterface. Exemplary materials of this nature are presently in commonuse for biopotential recording electrodes (e.g., for electrocardiographyand electroencephalography), as well as for electrodes used forfunctional electrical stimulation (e.g. for neuromuscular stimulation ortranscutaneous electric nerve stimulation for pain relief).

Where electrodes are used to deliver electrical stimulation, the pulsesmay be generated by oscillator/pulse generator circuits which deliverthe desired frequency, voltage, current, power, or other electricalpulse property to the electrode-skin interface. Skin stimulationgenerally involves voltages of 10-500 volts and currents of 0.5-50milliamps depending on factors such as electrode geometry and thelocation and condition of the site at which the electrode is to beplaced. For oral tissue stimulation, similar currents but lower voltagesof 1-40 volts may suffice. As previously noted, the stimulus waveformmay have a variety of time-dependent forms, and for cutaneous electricalstimulation, pulse trains and bursts of pulses have been found useful.Where continuously supplied, pulses may be 1-500 microseconds long andrepeat at rates from 1-1000 pulses/second. Where supplied in bursts,pulses may be grouped into bursts of 1-100 pulses/burst, with a burstrate of 1-100 bursts/second. A particularly effective cutaneous stimulususes 25-50 microsecond pulses repeating at a rate of 200 pulses/second,with every fourth pulse omitted to yield a 3 pulse/burst structure thatrepeats at 50 bursts/second.

As briefly discussed earlier, mechanical stimulation (if used) may bedelivered by various kinds of devices such as electromagnetic solenoids,shape-memory alloy (e.g. tin-nickel) actuators, piezoelectric actuators,electrically-active polymer actuators, electrorheological actuators,motors, electrostatic actuators, pneumatic or hydraulic cylinders orother devices, and micromechanical systems (MEMS) devices. Thestimulation devices may be held against the skin by masks, collars, andother devices as described above for use with electrodes. Preferably, amechanical actuator would be limited in size to agitate an area rangingbetween perhaps 1 square millimeter to 1 square centimeter of skin peractuator, but the size of the actuator (and thus the affected area) maybe larger or smaller as necessary; for example, it is possible toconstruct a mechanical actuator that provides mechanical stimulation toan entire large skin area (e.g., the entire face) at once, as by using avibrating rigid mask. The time dependency of mechanical stimulation istypically sinusoidal, with a rate of 1-1000 Hz and a displacement of 0.1micrometer to 5 millimeters, but different stimulationwaveforms/patterns may be used instead. A variation on mechanicalstimulation is the use of high-frequency (0.1-10 megahertz) ultrasonicstimulation which may be modulated to produce a varying “wave pressure”mechanical stimulation of subcutaneous nervous system tissue.

It is believed that stimulation of the trigeminal nerve (the fifthcranial nerve or CN-V) or branches thereof provides particularly rapidand potent rehabilitative effect, though it is possible that stimulationof parts of the body other than the head and neck—and thus nerves otherthan the trigeminal nerve—might work suitably well. Stimulation of thetongue affects the lingual nerve, a branch of the mandibular nerve(CN-V3), one of the three major divisions of the trigeminal nerve.Cutaneosensory information delivered to the lower lip, chin, jaw, andlower cheek up to the sides of the scalp also affects the mandibularnerve. Another major division of the trigeminal nerve, the maxillarynerve (CN-V2), receives cutaneosensory information from the region ofthe upper lip, lateral aspect of the nose, upper cheeks, below the eyes,and the temples. The final division of the trigeminal nerve, theopthalmic nerve (CN-V1), receives cutaneosensory information from theupper anterior two-thirds of the upper scalp, and the anterior third ofthe face that includes the forehead, nose, and regions above the eyes.

Stimulation of the facial nerve (CN-VII) or branches thereof is alsobelieved to be particularly beneficial, in part because such stimulationmay provide antidromic (backward) stimulation of the facial nervenucleus of the brainstem. Stimulation of the facial nerve can perhaps bemost easily effected via stimulation of the oral cavity; for example,when stimulation is provided to the tongue via a mouthpiece, the facialnerve is effectively stimulated via the chorda tympani (taste nerve), abranch of the facial nerve. However, stimulation of other branches ofthe facial nerve might also be effected by use of one or morestimulators situated on masks, collars, or other devices which fit overall or a portion of the face, or other areas of the head and/or neck.

Other regions for which stimulation may be particularly effectiveinclude the back of the head, the dorsal part of the neck, and themiddle of the shoulders. Stimulating these areas affects afferent nervesof the medial branches of the dorsal rami of the cervical spinal nerves(greater occipital-c2, occipital-c3, and c4-7, respectively). The areasabove and behind the ear (lesser occipital—c2,3), below the ear (greaterauricular—also c2,3), the anterior neck (transverse cervical—also c2,3),and beneath the jaw and chin (supraclavicular—c3,4) can also be useful.

A preferred methodology for therapeutically administering the inventionis briefly described above, and is now discussed in greater detail. Itshould be understood that this methodology is merely one which hasproven effective in preliminary testing, and that variations from thismethodology are possible, and are regarded as being encompassed by theinvention. The following steps of the methodology are preferablyperformed in the order presented below.

Initially, the patient is preferably queried to assess current healthand functional state (emotional, physical and cognitive). This mayinclude an oral interview and/or testing, and known and conventionalinterviews/tests such as the Short Form-36 (SF-36, for generalevaluation of physical and mental health), the Continuous CognitivePerformance Test (for measuring cognition/attention), the HamiltonDepression Scale (HAM-D, for measuring depression severity), the DynamicGait Index (for measuring gait and the likelihood of falling), theDizziness Handicap Index (DHI, for measuring the severity of vestibulardisorders), the Activities-specific Balance Confidence Scale (ABC, formeasuring fear of falling), the Multiple Sclerosis Impact Scale (MSIS,for measuring the severity of symptoms of multiple sclerosis), and/orother tools may be employed.

The patient may then be educated about the global, daily, andsession-specific objectives of the therapy. This may includefamiliarization with the stimulation routine, hardware, and software tobe used in the therapy. This can help to alleviate patient anxiety, andincrease cooperation and confidence.

The patient is then preferably physically conditioned within the limitsof the patient's (initial) ability, without any stimulation beingapplied, wherein the conditioning at least partially encompasses actionswhich are hindered by the patient's functional deficit. This can beuseful to familiarize the patient with the planned therapy for the day;to redevelop body awareness of potential ability and of unconsciousadaptations the patient may have made; and to give the therapist anestimation of the patient's degree of (and confidence in their)brain-body integration.

The patient may then be made to engage in a short (e.g., 5-minute)therapy period wherein the patient performs one or more tasks selectedto address the patient's functional deficit (i.e., tasks which arehindered by the patient's functional deficit), with the tasks beingperformed at a low intensity level while the patient simultaneouslyreceives stimulation. The task intensity is set at a low level to betterfamiliarize the patient with the routine they will be experiencingduring the remainder of the therapy session. This step helps buildfamiliarity with a task, and establishes confidence in task performance.This step may be followed by a short (e.g., 3-minute) rest period.

The patient then preferably engages in a short (e.g., 5-minute) therapyperiod wherein the patient performs the same task while receivingstimulation, with the task being modified to present a challenge that isslightly beyond the patient's current functional capacity. Thehigh-intensity challenge may require active reinforcement andredirection by the therapist to ensure the patient performs the taskcorrectly under new operating conditions, and that the patient does not(for example) rely on compensatory strategies that the patientestablished in response to the functional deficit. This step may befollowed by a short (e.g., 3-minute) rest period.

The patient can then engage in a short (e.g., 5-minute) therapy periodwherein the patient again performs the same task while receivingstimulation, with the task now being modified to present a moderatechallenge that is within the patient's current functional capacity. Thisfamiliarizes the patient with the moderate-intensity task. This step maybe followed by a short (e.g., 3-minute) rest period.

The patient then preferably engages in a longer therapy period (e.g., 20minutes) at the same moderate level, with the patient simultaneouslyreceiving stimulation. This period allows for a longer period duringwhich neural plasticity and rehabilitation is induced in the neuralstructures involved in performing the particular task.

Optionally, stimulation might then be applied (or continued) for a briefperiod of time while the patient is not engaged in the task. This may beuseful to continue stimulation of the neural structures involved inperforming the particular task (though other neural structures may bestimulated as well), and may help to enhance rehabilitation.

The patient may then engage in simplified post-therapy querying andassessment using metrics which are the same as or similar to those notedabove. This helps to quantify changes in functional capacity, and toassess the need for changes in the rate and type of therapy progression.No stimulation need be applied during this step.

These steps are preferably performed by a patient at least twice perday, with a period of at least 4 hours separating each session (i.e.,each set of steps). If more than one session is performed per day, someof the steps (e.g., the first and second steps) might be omitted for thesessions following the first one.

It is believed that the benefits of the invention are not limited toneurorehabilitation to at least partially restore impaired movement orphysical function, and that the benefits extend to other humancapabilities that depend on neurological function. In particular, it isbelieved that the benefits of the invention extend to at least partialrestoration of mental capabilities as well as physical capabilities. Forexample, rehabilitation of impaired cognitive (e.g. attention, memory,learning, multitasking, etc.) function may be improved by providingstimulation during tasks designed to exercise perceptual and cognitiveskills. Such tasks could include commonly available “brain-training”exercises or games, e.g., computerized or non-computerized exercises orgames designed to require use of attention span, memory/recollection,reading comprehension, etc. For example, a patient with memoryimpairment due to Alzheimer's disease might perform a set of memoryexercises of progressively greater difficulty in conjunction withstimulation, thereby functionally and structurally improving memorycircuitries via induced synaptic plasticity. Beneficially, mentalexercises of this nature can be readily delivered to a patient viacomputer (as in the nature of tests, puzzles, or other queries directedto the patient via a computer screen or other output device), with thecomputer collecting the patient's responses, thereby reducing the needfor (and expense of) therapist involvement. Because the benefits ofstimulation are not specific to any particular disease mechanism, theymay be beneficial for a wide range of degenerative, traumatic, ordegenerative causes of cognitive impairment, including (but not limitedto) Parkinson's disease, multiple sclerosis, stroke, head trauma, autismand cerebral palsy.

As another example, it is believed that the invention can providebenefits for at least some type of mood disorders, e.g. depression,anxiety, bipolar disorder, schizophrenia, post-traumatic stressdisorder, obsessive-compulsive disorder, etc. In these cases, the tasksperformed by the patient might include those that are commonly usedduring therapies for mood disorders, e.g. cognitive-behavioral therapyexercises, progressive exposure to “triggers” for compulsive behaviors,visualization exercises, meditation, relaxation techniques, etc. Heretoo stimulation may enhance functional and structural plastic changesassociated with the therapeutic task, causing the new behaviorspracticed during the therapy to become more automatic.

It is further believed that the invention can also assist in theenhancement of nonimpaired physical and/or mental capabilities, as wellas assisting in at least partial restoration of impaired physical and/ormental capabilities. Thus, the invention might assist with proficiencyin physical and/or mental activities such as sports activities,reading/studying, playing of a musical instrument, etc. in “patients”who do not have any recognized impairment in these fields. As forpatients having impaired neurological states, the combination ofstimulation and practicing the particular task (physical, cognitive orpsychological) will enhance the plastic learning response of the areasand systems of the brain engaged in performance of that task.

It is also emphasized that the application of stimulation is believed tobe beneficial where the stimulation is applied prior to and/or afterperformance of tasks, as well as during performance of such tasks.Application of stimulation before, during, and/or after any task willpotentially enhance the efficiency (and efficacy) of neural circuitriesresponsible for performance of that task, by changing the neuro-chemicalenvironment, the physical structure, and/or other physiological aspectsof these neural circuitries. For example, stimulation before the taskmay create chemical changes that prime the neural tissue to be morereceptive to plastic changes; stimulation during the task may increasethe baseline neural activity to enhance the plastic response to taskperformance; and stimulation after the task may enhance consolidation ofstructural and functional changes related to the task.

It should be understood that the versions of the invention describedabove are merely exemplary, and the invention is not intended to belimited to these versions. Rather, the scope of rights to the inventionis limited only by the claims set out below, and the inventionencompasses all different versions that fall literally or equivalentlywithin the scope of these claims.

What is claimed is:
 1. A method of providing non-invasiveneurostimulation to enhance a subject's proficiency in an exercisecomprising: (a) engaging a subject in an exercise, the subject having nocognitive, physical or emotional impairment with respect to theexercise; (b) providing stimulation of at least one of the subject'strigeminal nerve, facial nerve or hypoglossal nerve by deliveringelectrical pulses generated by a signal generator to the subject's oralcavity via at least one electrode in contact with a region within thesubject's oral cavity, the delivery of electrical pulses being (i)contemporaneously with and independent of the subject's engagement inthe exercise, and (ii) independent of the subject's surroundingenvironment; and (c) repeating steps (a) and (b) on a periodic basis. 2.The method of claim 1 wherein the exercise comprises one or more of aphysical activity, a sports activity, reading, studying, playing amusical instrument, operating a vehicle, sleep or relaxation.
 3. Themethod of claim 1 wherein the exercise includes one or more of thefollowing: a brain training exercise, a computerized brain trainingexercise, a memory recollection exercise, an attention span increasingexercise, or a reading comprehension exercise.
 4. The method of claim 1wherein step (b) further comprises providing stimulation during one ormore of a period shortly or immediately before the subject has engagedin the exercise, or a period shortly or immediately after the subjectengaged in the exercise.
 5. The method of claim 1 wherein the deliveryof electrical pulses is in a random or repeating pattern that isindependent of events occurring outside the signal generator.
 6. Themethod of claim 1 wherein the at least one electrode is part of anelectrode array.
 7. The method of claim 1, wherein the stimulation isprovided to the subject's tongue.
 8. A method of providing non-invasiveneurostimulation to enhance a subject's proficiency in an exercisecomprising: (a) engaging a subject in an exercise, the subject having nocognitive, physical or emotional impairment with respect to theexercise; and (b) providing stimulation of at least one of the subject'strigeminal nerve, facial nerve or hypoglossal nerve by deliveringelectrical pulses to a region of the subject's oral cavity via at leastone electrode in contact with the region of the subject's oral cavity,the delivery of electrical pulses being (i) contemporaneously with andindependent of the subject's engagement in the exercise, and (ii)independent of the subject's surrounding environment.
 9. The method ofclaim 8 wherein the stimulation is generated by a signal generator. 10.The method of claim 8 wherein the exercise comprises engaging thesubject in one or more of a physical activity, a sports activity,reading, studying, playing a musical instrument, sleep or relaxation.11. The method of claim 8 further comprising repeating steps (a) and (b)on a periodic basis.
 12. The method of claim 8, wherein the stimulationis provided to the subject's tongue.
 13. A method of providingnon-invasive neurostimulation to enhance proficiency in an exercise, themethod comprising: (a) providing an exercise regimen including theexercise for use by a subject having no cognitive, physical or emotionalimpairment with respect to the exercise; and (b) providing stimulationconfigured to excite at least one of the subject's trigeminal nerve orthe subject's facial nerve by delivering electrical pulses to a regionwithin the subject's oral cavity via at least one electrode in contactwith the region within the subject's oral cavity; wherein the deliveryof electrical pulses is configured to be (i) contemporaneous with andindependent of the subject's engagement in the exercise, and (ii)independent of the subject's surrounding environment.
 14. The method ofclaim 13 wherein the electrical pulses are generated by a signalgenerator.
 15. The method of claim 13 wherein the exercise includes oneor more of a physical activity, a sports activity, reading, studying,playing a musical instrument, operating a vehicle, sleep or relaxation.16. The method of claim 13 wherein the stimulation occurs during one ormore of a period shortly or immediately before the subject has engagedin the exercise, or a period shortly or immediately after the subjectengaged in the exercise.
 17. The method of claim 13 wherein thestimulation is unsynchronized with the subject's engagement in theexercise.
 18. The method of claim 13 wherein the stimulation includeselectrical pulses delivered to the one or more stimulators in a randomor repeating pattern that is independent of the subject's engagement inthe exercise.
 19. The method of claim 13 wherein the exercise regimenincludes (i) performing the exercise at high intensity; and (ii)subsequently performing the exercise at moderate intensity.
 20. Themethod of claim 19 wherein the exercise regimen includes performing theexercise at low intensity before performing the exercise at highintensity.
 21. The method of claim 13 wherein the at least one electrodeis part of an electrode array.
 22. The method of claim 13, wherein thestimulation is provided to the subject's tongue.